The Food and Drug Administration is still investigating whether the death last summer of a 36-year-old Illinois woman was directly caused by an experimental gene therapy procedure. Jolee Mohr was enrolled in a gene transfer clinical trial for arthritis, sponsored by Targeted Genetics Corporation of Seattle. She developed a fever of 105 degrees and multiple organ failure just after she received a second injection of genes carried by engineered viruses.

The story is complicated and still unfolding. The Recombinant DNA Advisory Committee (RAC), which oversees gene transfer protocols for the National Institutes of Health (NIH), discussed Mohr's death in September 2007 and will return to it at its December meeting. The information publicly available from news reports and the RAC meeting strongly suggests that the gene transfer experiment was at the very least a significant contributing factor.

What do we know at this point about what went wrong? Is Mohr's death an isolated tragedy? Or is it a symptom of deeper problems with the way gene transfer experiments are being conducted?

In the 1980s and 1990s, gene therapy was widely touted - with virtually no clinical proof - as a medical miracle. Some called it a cure for cancer in an injection. Others predicted that it would enable the conquest of many others of our most serious diseases. The first experimental gene-based treatments were administered in 1990, with inconclusive results.

Since then, gene transfer researchers have conducted hundreds of clinical trials, received hundreds of patents, written thousands of articles, and launched scores of companies. In a 2005 article in Human Gene Therapy, Christine Crofts and Sheldon Krimsky commented that the size and strength of this infrastructure is "seemingly incommensurate with the demonstrated potential of the technique."

More bluntly, the record of gene transfer has been worse than disappointing. In truth, gene therapy has harmed more people than it has helped.

Who should participate in gene therapy experiments?

Jolee Mohr had arthritis. While for some people arthritis is debilitating, it is not life-threatening. Mohr's husband Robb Mohr has said that she suffered from "occasional stiffness," and that she went boating the weekend before she was injected with genetically engineered viruses.

In 2000, after the gene transfer death of 18-year-old Jesse Gelsinger - in a clinical trial for a condition that he was able to control with a conventional treatment - one of us (Newman) appeared before the RAC to request that they limit enrollment in gene therapy protocols to people with serious conditions that cannot be treated by other methods. This would have required a reformulation of the existing multi-phase clinical framework which, though useful for pharmaceutical drug evaluations, has severe limitations in other applications. Although one long-term committee member privately expressed his strong support for the proposal, the public discussion that day was entirely dismissive.

If the RAC had followed this recommendation, researchers could have spent the past seven years testing gene transfer in situations where the risks were far better justified. Mohr wouldn't have been a candidate for experimental gene transfer, and probably would be alive today.

Do participants in clinical trials benefit from them?

The clinical trials in which Gelsinger and Mohr participated were both early-phase studies, which are designed to evaluate the safety of experimental treatments. They are explicitly not meant to assess effectiveness. But Mohr was under the impression, her husband said, that the treatment would "make her knee better."

Hope for a cure strongly motivates a person to assume risks. That's why it is - or should be - a cornerstone of medical ethics to ensure that participants in early-phase clinical studies fully understand not to expect any therapeutic benefit from them.

What led Mohr to enter the study, then? The fact that her own doctor invited her to participate may well have contributed to her misunderstanding. Trust in our doctors to help us - or at least to "do no harm" - is likely to outweigh the fine print in a release form. The consent agreement used in the Targeted Genetics arthritis study contained a single sentence saying that no medical benefits were anticipated, along with long descriptions of how the product might help.

Mohr's doctor - rheumatologist Robert Trapp of The Arthritis Center in Springfield - may have had no reason to believe that the experimental treatment would harm her. But it turns out that his clinic received payments from Targeted Genetics for each subject he recruited. Studies show that doctors are influenced even by small gifts from drug companies. Should we allow them to receive direct financial payments to recruit their patients into trials that carry significant risks?

Who makes the rules?

The RAC, established to provide oversight for gene transfer, has always made its deliberations and the researchers' responses to them publicly available. But the FDA, to which actual authority for gene therapy experiments was transferred in the mid-1990s, considers most information about adverse reactions to be the property of the sponsoring company. Paul Gelsinger, Jesse's father, recalls an FDA representative telling indignant RAC members, "My superiors answer to industry."

In 2003, the RAC - now a purely advisory body - evaluated Targeted Genetics' arthritis study. Committee members questioned the justification for the trial, both because it involved patients who were not very ill and because evidence from animal studies didn't show much improvement. They worried that the viruses and the genes they carried could trigger dangerous immune system responses. They criticized the informed consent document for not being clear enough about the fact that participants in the trial would be unlikely to get any benefit from it.

Targeted Genetics addressed some of these concerns in remarks at the 2003 meeting. But because resolution of issues discussed before the RAC was a matter for the FDA and thus no longer part of the public record, there is no way to know the extent to which the company was responsive.

Conflicts of interest?

The products of biomedical and biotech companies are often matters of life and death. They are also matters of profit and loss.

In the study in which Gelsinger was enlisted, both principal investigator James Wilson and his academic employer, the University of Pennsylvania, had financial stakes in a biotech company called Genovo, Inc. Wilson and the university stood to make money, perhaps a lot of it, if the experimental treatment could be commercialized. The investigations that followed Gelsinger's death disclosed dangerous shortcuts and clear-cut ethical violations in that study. These findings were strong enough to lead to extensive reforms in the financing of research at Penn and many other universities.

Were any similar dynamics at play in the arthritis study? In 2005, Targeted Genetics CEO H. Stewart Parker told a Seattle newspaper that her company's gene transfer system for arthritis was aimed at "a $7 billion market...by 2011" and that she was "looking at 15 to 40 percent of that opportunity." Targeted Genetics (which purchased Genovo in 2000 in a deal that gave James Wilson $13.5 million in stock for his 30% share) clearly wants to get its gene transfer product to market. One important step in that process is enrolling subjects for its clinical trials as rapidly as possible. Could financial pressures created by expectations of a lucrative market have endangered study participants?

What now?

There are still many unanswered questions about this latest gene transfer death. But two lessons seem clear.

First, regulators should rethink the drug-related multi-phase clinical trial model for testing genetic agents. Moving towards a model in which subjects are chosen on a "compassionate use" basis, in cases where there are no good alternatives, may not ideally suit commercial prerogatives. But in linking testing to the possibility of actual therapy, it may be good medicine, and because it is subject-oriented, ultimately more ethical. There is no question that valid scientific data can be extracted from such studies, despite their complexities.

Second, we need much greater transparency in the conduct of clinical trials, whether they're conducted at universities and medical schools, or sponsored by commercial enterprises. In the present instance, the FDA should make public complete information about the Targeted Genetics arthritis gene transfer trials. This means not just officially confirming the cause of Mohr's death, but also making public information about how Mohr (and other participants) came to be enrolled in the trial, whether they received independent medical advice and care, and releasing all records relevant to the issue of whether and how Targeted Genetics addressed the concerns raised by RAC members in 2003.

Clinical research is a major function of medical schools and collaborating university departments in basic and social sciences, relating to their roles in the production of knowledge and the education of physicians and scientists. It has also been a mainstay in the funding of such institutions since the end of World War II in the form of overhead from Federal grants and, increasingly since the 1980s, in the form of commercial investment in anticipation of revenues from patentable products of the research. Distortions of academic functions are inevitable when the financial aspect looms so large, and have been well documented (Washburn, 2005). Distortions of the medical function, with loss of life one of the consequences, are unfortunately no longer rare.

The precedents set by the FDA's handling of the Mohr tragedy will have ramifications beyond gene transfer experiments. The level of protection the agency offers to human subjects will affect the safety of experiments with new drugs, new medical devices, and novel medical approaches such as stem cell treatments.

Prospective patients and the public need to keep in mind that clinical trials often involve risks to participants - and significant financial stakes for researchers, companies, and sometimes their own doctors.

Anyone who puts profit before patient safety must be held to account. And government regulators must answer not just to industry but, above all, to patients and the public.

Marcy Darnovsky, Ph.D., is Associate Executive Director at the Center for Genetics and Society, an Oakland, California-based public interest organization working to encourage the responsible use and effective governance of human biotechnologies.

Stuart Newman, Ph.D., is Professor of Cell Biology and Anatomy at New York Medical College and a founding member of the Council for Responsible Genetics.

References

1. Christine Crofts and Sheldon Krimsky, "Emergence of a Scientific and Commercial Research and Development Infrastructure for Human Gene Therapy," Human Gene Therapy 16:169-177 (February 2005)

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